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The overall goal of this project is to advance the understanding of underlying mechanisms impacting performance fatigability and perceived fatigability in Veterans with post-COVID-19 fatigue and explore the safety and feasibility of a home-based "minimal-dose" resistance exercise program in this population. The central hypothesis is that declines in force capacity, skeletal muscle oxygen extraction, and affective responses to physical activity offer potential mechanisms through which fatigability is increased in Veterans with post-COVID-19 fatigue. Moreover, home-based resistance exercise delivered remotely may provide a safe and feasibility treatment option for targeting neuromuscular and neurobehavioral factors influencing fatigability severity in this population.
The clinical case definition of post-COVID-19 condition (also referred to as Long COVID) as defined by the World Health Organization (WHO) includes individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis. Fatigue represents one of the most frequently reported symptoms in individuals experiencing post-COVID-19 (i.e., post-COVID-19 fatigue; PCF).Fatigue is shown to persist for months after SARS-CoV-2 infection, negatively impacting activities of daily living. For the purposes of this SPiRE proposal, fatigue is operationally defined as a state characteristic encompassing a subjective lack of physical and/or mental energy that is perceived by the individual to interfere with usual or desired activities.
Increased fatigability is a possible complication following SARS-CoV-2 infection due to the presence of both neuromuscular and neurobiological consequences. Skeletal muscle alterations including reduced force capacity, fiber atrophy, mitochondria and metabolic dysfunction, and capillary impairments have been observed in patients following SARS-CoV-2 infection. Autopsy reports of patients who died after SARS-CoV-2 infection found evidence of skeletal muscle atrophy of type 2 fibers, necrotizing myopathy, and myositis. Similarly, using nerve conduction studies, patients with long-term COVID-19 were found to have signs of myopathy, even those who were not hospitalized. Evidence from cardiopulmonary exercise testing in patients diagnosed with COVID-19 has revealed impaired skeletal muscle oxygen extraction, as opposed to central limitations (i.e., cardiac output), as a determinant of exercise intolerance. In addition to neuromuscular complications, SARS-CoV-2 infection has also been shown to be associated with psychiatric sequelae. Collectively, these findings underscore neuromuscular as well as neurobiological consequences of SARS-CoV-2 as potential independent or co-occurring mechanisms by which increased fatigability occurs and persists.
Despite widespread calls for the importance of rehabilitation in individuals recovering from SARS-CoV-2 infection, little progress has been made regarding the potential benefits of physical exercise on fatigue and fatigability in this population. Moreover, concerns have been raised about the applicability of physical exercise in patients recovering from SARS-CoV-2 infection. For example, while the health and functional benefits of exercise are vast and widely known, in certain patient populations exertion is shown to exacerbate symptom severity. Some individuals with PCF may report experiencing worsening of symptoms after physical or mental exertion. Home-based exercise may offer an appealing option for those individuals concerned about attending community fitness facilities. Home-based exercise is shown to produced moderate effects on muscle strength and balance. Presently, the exact dosing of home-based exercise to elicit positive outcomes in fatigability is unknown. Minimal-dose resistance exercise has been proposed as a potential strategy for improving neuromuscular characteristics and physical function. Minimal-dose resistance exercise uses little to no equipment with exercises performed at lower workloads. The investigators aim to adapt the "minimal-dose" resistance exercise paradigm to a remote home-based resistance exercise program for Veterans with PCF to determine its implications for reducing fatigability and improving neuromuscular and neurobiological factors. Minimal-dose resistance exercise for the proposed application is defined as a single, weekly body-weight exercise session.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Minimal-Dose Home-Based Resistance Exercise | Experimental | 8-week home-based resistance exercise performed one day per week. |
|
| Standard of Care | No Intervention | Subjects will be asked to follow standard of care recommendations as prescribed by the physician. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Minimal-Dose Home-Based Resistance Exercise | Behavioral | 8-week home-based resistance exercise performed one day per week. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Performance fatigability | Performance fatigability will be assessed as change in maximal voluntary isometric contraction (MVIC) torque of the dominant leg. Change in MVIC torque from the initial MVIC contraction to the last MVIC contraction will be used to determine the Performance Fatigability index. | baseline and week 8 |
| Measure | Description | Time Frame |
|---|---|---|
| Rating of Perceived Fatigue (RPF) | Perceived fatigability will be assessed using a rating of perceived fatigue (RPF) scale. 0=no fatigue at all; 10=absolutely exhausted higher the value=more fatigue | baseline and week 8 |
| Isometric and Isokinetic Knee Extensor Torque |
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Inclusion Criteria:
ambulatory patients (with or without a gait aid)
50 years of age or older
with a confirmed diagnosis of COVID-19 by polymerase chain reaction (PCR) test, antibody test or clinical diagnosis
the symptom of fatigue reported greater than 12-weeks post-infection (reporting fatigue: yes/no)
receiving care at the DC VAMC
the ability to speak and read English, and orientation to person, place, and time
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jared M. Gollie, PhD | Washington DC VA Medical Center, Washington, DC | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Washington DC VA Medical Center, Washington, DC | Washington D.C. | District of Columbia | 20422-0001 | United States |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| ICF | No | No | Yes | Informed Consent Form | Mar 3, 2025 | Aug 28, 2025 | ICF_000.pdf |
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| ID | Term |
|---|---|
| D000094024 | Post-Acute COVID-19 Syndrome |
| D005221 | Fatigue |
| D000086382 | COVID-19 |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
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Randomized controlled pilot study
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Unilateral peak isometric and isokinetic knee extension torque (60º/s and 180º/s) will be obtained across five continuous repetitions using a dynamometer in a seated position per manufacturer guidelines (Biodex System 4). |
| baseline and week 8 |
| Skeletal muscle oxygen extraction | Skeletal muscle oxygen extraction of the dominant vastus lateralis will be assessed non-invasively using near-infrared spectroscopy (NIRS) (Artinis, Portamon, The Netherlands). | baseline and week 8 |
| Feeling Scale | Change's in affect during knee extensor performance fatigability testing will be assessed using the Feeling Scale. The Feeling Scale is an 11-point, single item, bipolar rating scale ranging from +5 to -5. | baseline and week 8 |
| Fatigue Severity Scale (FSS) | 9-item questionnaire assessing how fatigue interferes with certain activities and rates its severity according to a self-report scale. Items are scored on a 7-point scale with 1=strongly disagree and 7=strongly agree. higher the value=more impact fatigue has | baseline and week 8 |
| Short Physical Performance Battery (SPPB) | SPPB will assess customary gait speed, side-by-side stand, semi-tandem stand, tandem stand, and 5-STS. | baseline and week 8 |
| 30-second sit-to-stand | subjects will be asked to perform as many sit-to-stand repetitions in 30 seconds. | baseline and week 8 |
| Six Minute Walk Test (6MWT) | Subjects will be asked to walk as far as possible in 6 minutes. | baseline and week 8 |
| Motor Unit Firing Rate | motor unit shape and firing behavior of the dominant leg vastus lateralis will be extracted using surface electromyographic signals (sEMG) and specialized software (Trigno NeuroMap System, Delsys Inc., Natick, MA, USA). | baseline and week 8 |
| Muscle Activation | interpolated twitch technique will be applied to the femoral nerve using a constant-current, variable high-voltage stimulator (DS7R, Digitimer, Hertforshire, UK) to quantify muscle activation of the vastus lateralis. | baseline and week 8 |
| peak VO2 | Peak VO2 will be assessed from cardiopulmonary exercise testing using the Modified Bruce Protocol. | baseline and week 8 |
| Health-related quality of life (SF-36) | The 36-item short-form (SF-36) is a multi-item scale that assesses eight health concepts: 1) limitations in physical activities because of health problems; 2) limitations in social activities because of physical or emotional problems; 3) limitations in usual role activities because of physical health problems; 4) bodily pain; 5) general mental health (psychological distress and well-being); 6) limitations in usual role activities because of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions. | baseline and week 8 |
| Pittsburgh Fatigability Scale | 26-item scale chosen from four activity categories; social, sedentary, lifestyle or light-intensity, and moderate-to-high-intensity. | baseline and week 8 |
| Short-form Depression, Anxiety, and Stress Scale (DASS-21) | The DASS is designed to measure the negative emotional states of depression, anxiety, and stress. | baseline and week 8 |
| Physical Activity Level | Physical activity levels will be monitored objectively using ActiGraph activity monitors | baseline and week 8 |
| D014777 |
| Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D000094025 | Post-Infectious Disorders |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012816 | Signs and Symptoms |